Method for the treatment of urinary incontinence

ABSTRACT

Urinary incontinence is alleviated in a mammal by administering to the mammal a urinary incontinence alleviating amount of dextromethorphan, dextrorphan, their mixtures and/or pharmaceutically acceptable salts, alone or in combination with a pharmacologically active agent such as an anticholinergic, sympathomimetic, tricyclic antidepressant, antispasmodic, direct-acting smooth muscle relaxant, estrogen, compound having estrogen-like activity, or any combination of the foregoing.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a method for treating urinaryincontinence.

[0003] 2. Description of Related Art

[0004] Urinary incontinence is a fairly common medical problem in whichurine is involuntarily lost. Urinary incontinence may be transient orpersistent. Common causes of transient urinary incontinence includeinfection, atrophic urethritis, administration of diuretics anddelirium. Persistent urinary incontinence is classified into four types:(1) stress incontinence which involves involuntary loss of urine duringcoughing, sneezing, laughing, or other physical activity; (2) urgeincontinence which involves involuntary loss of urine associated with anabrupt or strong desire to void; (3) overflow incontinence whichinvolves involuntary loss of urine associated with over-distension ofthe bladder; and (4) mixed incontinence which involves a combination ofat least two of the above types.

[0005] Persistent urinary incontinence can result from spastic orhyperactive bladder smooth muscle such as detrusor originatingincontinence. In certain instances such incontinence is caused by lossof control resulting from spinal injury, parkinsonism, multiplesclerosis or recurrent bladder infection to name a few. Treatment ofincontinence may involve surgery or administration of any of variouspharmacological agents, e.g., a anticholinergic such as oxybutynin,atropine, propantheline, terodiline, dicyclomine and others, asympathomimetic such as ephedrine, pseudoephedrine, phenylpropanolamineand others, a tricyclic antidepressant such as amitriptyline,imipramine, doxepin and others, an estrogen or a direct actingantispasmodic such as flavoxate. In addition to treating incontinence,such pharmacological agents may cause other powerful physiologicresponses such as excitability (sympathomimetics), and dry mouth,drowsiness, dizziness or hallucinations (anticholinergics or tricyclicantidepressants).

[0006] Other compounds described as useful for treating urinaryincontinence are described, e.g., in U.S. Pat. Nos. 4,645,758,4,865,843, 5,080,905, 5,236,956, 5,233,053, 5,252,589, 5,258,390,5,272,163, 5,340,805, 5,340,819, 5,340,826, and 5,266,596. U.S. Pat. No.5,192,751 describes the use of certain competitive N-methyl-D-aspartate(NMDA) receptor antagonists in the treatment of urinary incontinence. Itis noted therein that a non-competitive NMDA receptor antagonist,MK-801, has been reported to produce an increase in frequency inmicturition (Vera et al., Neurosci. Lett., 134, 135-138 (1991)).

[0007] Dextromethorphan and its main metabolite, dextrorphan, arenon-competitive NMDA receptor antagonists having few, if any, sideeffects at indicated dosage levels. Dextromethorphan and dextrorphanhave been used as antitussives, for treatment of chronic pain (U.S. Pat.No. 5,352,683) and for inhibiting the development of tolerance to and/ordependence on a narcotic analgesic (U.S. Pat. No. 5,321,012).Surprisingly, it has now been found that the non-competitive NMDAreceptor antagonists dextromethorphan and dextrorphan are useful in thetreatment of urinary incontinence.

SUMMARY OF THE INVENTION

[0008] In accordance with the present invention, there is provided amethod for the treatment of urinary incontinence which comprisesadministering to a mammal exhibiting urinary incontinence a urinaryincontinence alleviating amount of at least one morphinan selected fromthe group consisting of dextromethorphan, dextrorphan andpharmaceutically acceptable salts thereof. The method can optionallyinclude administration of one or more pharmacologically active agentsselected from the group consisting of anticholinergics,sympathomimetics, tricyclic antidepressants, antispasmodics, directacting bladder smooth muscle relaxants, estrogens, compounds havingestrogen-like activity, and any combination of the foregoing.

[0009] In another embodiment of the present invention, there is provideda method of decreasing micturition frequency in a mammal which comprisesadministering to a mammal a micturition decreasing amount of at leastone morphinan selected from the group consisting of dextromethorphan,dextrorphan and pharmaceutically acceptable salts thereof. The methodcan optionally include administration of any of the pharmacologicallyactive agents mentioned above.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In the accompanying drawings:

[0011]FIG. 1 is a graphical representation of test results showingtherapeutic effects of intravenous administration of dextromethorphan onabsolute micturition pressures in rats; and,

[0012]FIG. 2 is a graphical representation of test results showingtherapeutic effects of intravenous administration of dextromethorphan onmicturition frequency in rats.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Dextromethorphan ((+)-3-methoxy-N-methylmorphinan) anddextrorphan ((+)-3-hydroxy-N-methylmorphinan), their mixtures andpharmaceutically acceptable salts are utilized in accordance with themethod of the present invention. Accordingly, dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts areadministered by any known route of administration for the relief ofsymptoms of bladder instability associated with voiding in patients withuninhibited neurogenic or reflex neurogenic bladder such as urgency,frequency, urine leakage, urge incontinence, stress incontinence,overflow incontinence, mixed incontinence or dysuria. Dextromethorphan.,dextrorphan, their mixtures and/or pharmaceutically acceptable salts arealso useful in the treatment of interstitial cystitis, a chronicinflammatory condition of unknown etiology resulting in reduced bladdercapacity and severe bladder irritative symptoms. Administration ofdextromethorphan, dextrorphan, their mixtures and/or pharmaceuticallyacceptable salts acts to quiet the bladder and reduce the frequency ofmicturition.

[0014] Administration of dextromethorphan, dextrorphan their mixturesand/or pharmaceutically acceptable salts can be orally or transdermallyor by intravenous, intramuscular, subcutaneous, intrathecal, epidural orintracerebro-ventricular injection. Effective dosage levels can varywidely, e.g., from about 0.25 to about 250 mg/day, but actual amountswill, of course, depend on the state and circumstances of the patientbeing treated. As those skilled in the art recognize, many factors thatmodify the action of the active substance herein will be taken intoaccount by the treating physician such as the age, body weight, sex,diet and condition of the patient, the time of administration, the rateand route of administration, and so forth. Optimal dosages for a givenset of conditions can be ascertained by those skilled in the art usingconventional dosage determination tests in view of the experimental dataprovided herein.

[0015] Therapeutic compositions containing dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable saltswill ordinarily be formulated with one or more pharmaceuticallyacceptable ingredients in accordance with known and establishedpractice. Thus, dextromethorphan, dextrorphan,, their mixtures and/orpharmaceutically acceptable salts can be formulated as a liquid, powder,elixir, injectable solution, etc. Formulations for oral use can beprovided as hard gelatin capsules wherein dextromethorphan, dextrorphan,their mixtures and/or pharmaceutically acceptable salts are mixed withan inert solid diluent such as calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts aremixed with an oleaginous medium, e.g., liquid paraffin or olive oil.

[0016] Aqueous suspensions can contain the dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts inadmixture with pharmaceutically acceptable excipients such as suspendingagents, e.g., sodium carboxymethyl cellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; dispersing or wetting agents such asnaturally occurring phosphatide, e.g., lecithin, or condensationproducts of an alkaline oxide with fatty acids, e.g., polyoxyethylenestearate, or condensation products of ethylene oxide with long chainaliphatic alcohols,, e.g. heptadecaethylene-oxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol, e.g., polyoxyethylene sorbitol monoleate or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate. Suchaqueous suspensions can also contain one or more preservatives, e.g.,ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, saccharin or sodium or calcium cyclamate.

[0017] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide dextromethorphan,dextrorphan, their mixtures and/or pharmaceutically acceptable salts inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, e.g., sweetening, flavoring and coloring agents,can also be present. Syrups and elixirs can be formulated withsweetening agents, for example glycerol, sorbitol or sucrose. Suchformulations can also contain a demulcent, a preservative and flavoringand coloring agents.

[0018] Dextromethorphan, dextrorphan, their mixtures and/orpharmaceutically acceptable salts are advantageously provided insustained release dosage form of which many kinds are known, e.g., asdescribed in U.S. Pat. Nos. 4,788,055; 4,816,264; 4,828,836; 4,834,965;4,834,985; 4,996,047; 5,071,646; and, 5,133,974, the contents of whichare incorporated by reference herein.

[0019] It is also within the scope of this invention to administerdextromethorphan, dextrorphan, their mixtures and/or pharmaceuticallyacceptable salts prior to, concurrently with, or after administration ofany other known pharmacologically active agent useful for treatingurinary incontinence. Such agents include, but are not limited to,anticholinergics such as oxybutynin, atropine, propantheline,terodiline, dicyclomine, etc., sympathomimetics such as ephedrine,pseudoephedrine, epinephrine, phenylpropanolamine, etc., tricyclicantidepressants such as imipramine, doxepin, amitriptyline, etc.,estrogens or estrogen-related compounds having estrogen-like activitysuch as estradiol, estrone, etc., and antispasmodics or direct actingbladder smooth muscle relaxants such as flavoxate. For a detaileddiscussion of these pharmacologically active agents, reference may bemade to “Goodman and Gillman's Pharmacological Basis of Therapeutics”,Goodman et al., eds. 7th ed., 1985, Macmillan and Company, New York.

[0020] The examples that follow are illustrative of the presentinvention and should not be construed as limiting.

EXAMPLE 1

[0021] Ten female Sprague-Dawley rats having a mean weight of 263±19 gwere anesthetized with urethane (1.2 g/k, sc.). A midline incision wasperformed to expose the bladder and a 23G catheter was inserted into thebladder dome for the measurement of intravesical pressure. A non-stoptransvesical cystometrogram, as described in J. Pharmacological.Methods, 15, pp. 157-167 (1986), was used, at a filling rate of 0.216ml/min. of saline, to access the filling and voiding characteristics ofthe bladder. Through the continuous cystometry method thus afforded,consecutive micturition could be recorded. Dextromethorphan was given atintravenous does of: 1.0, 3.0, 10, 30, 50 mg/kg after the initialbaseline micturition sequence was reliably measured for approximately 12min.. From these recordings the absolute values in maximum pressureobtained and the frequency of micturition was measured. A dose responsecurve illustrating the effect of dextromethorphan on the absolutemicturition pressures in the range of 1-50 mg/kg is given in FIG. 1.Data given are mean and SE.

[0022] The volume evoked micturition reflex was suppressed in a dosesensitive manner as seen from the effect of increasing doses ofdextromethorphan on the cystometrogram. In particular it was found thatat doses in the range of 10-30 mg/kg, the volume evoked micturitioncontractions are almost totally suppressed. A significant sustainedreduction in detrusor pressure is produced at a dose level of 3 mg/kgand a 50% reduction is evident at 10 mg/kg. As shown in FIG. 1, athigher doses of dextromethorphan, the rate of decrease in detrusorpressure is diminished. Furthermore at does higher than 10 mg/kg theeffect of the drug appears to be bimodal, producing an initial increasein detrusor pressure before suppression.

[0023] The corresponding dose response effect of dextromethorphan on thefrequency of micturition is given in FIG. 2. As shown, the frequency ofmicturition decrements gradually with respect to dose when compared tothe pressure.

EXAMPLE 2

[0024] A capsule containing dextromethorphan hydrobromide contains thefollowing ingredients: Ingredient mg/Capsule DextromethorphanHydrobromide USP 20 Pregelatinized Starch NF 50 Colloidal SiliconDioxide 1.5

EXAMPLE 3

[0025] A tablet containing dextromethorphan hydrobromide contains thefollowing ingredients: Ingredient mg/Tablet DextromethorphanHydrobromide USP 20 Microcrystalline Cellulose NF 17 Lactose NFanhydrous 68 Croscarmellose NF 1 Colloidal Silicon Dioxide 1.5 MagnesiumStearate NF 1.5

EXAMPLE 4

[0026] A controlled release tablet containing dextromethorphanhydrobromide contains the following ingredients: Ingredient mg/TabletDextromethorphan Hydrobromide USP 40 Lactose NF 70 Methocel E 15LV 100Ethylcellulose NF 35 Magnesium Stearate NF 15 Colloidal Silicon DioxideNF 2

[0027] The embodiments and examples given above are illustrative of thepresent invention. Consequently it should be understood thatmodifications can be made by those with ordinary skill in the art thatare intended to be covered by the following claims.

What is claimed is:
 1. A method of treating urinary incontinence whichcomprises administering to a mammal exhibiting urinary incontinence aurinary incontinence alleviating amount of at least one morphinanselected from the group consisting of dextromethorphan, dextrorphan andpharmaceutically acceptable salts thereof.
 2. The method of claim 1wherein the morphinan is contained in a pharmaceutically acceptablevehicle.
 3. The method of claim 1 therein the morphinan is provided insustained release dosage form.
 4. The method of claim 1 wherein themorphinan is administered orally, intravenously, intramuscularly,subcutaneously, transdermally or intrathecally.
 5. The method of claim 1which further comprises administering a pharmacologically active agentselected from the group consisting of anticholinergic, sympathomimetics,tricyclic antidepressants, antispasmodics, direct-acting bladder smoothmuscle relaxants, estrogens, compounds having estrogen-like activity,and any combination of the foregoing.
 6. The method of claim 5 whereinthe pharmacologically active agent is selected from the group consistingof oxybutynin, atropine, propantheline, terodiline, dicyclomine,ephedrine, pseudoephedrine, phenylpropanolamine, amitriptyline,imipramine, doxepin, an estrogen and flavoxate.
 7. The method of claim 5wherein the morphinan is administered concurrently with thepharmacologically active agent.
 8. The method of claim 7 wherein themorphinan and pharmacologically active agent are contained in apharmaceutically acceptable vehicle.
 9. The method of claim 5 whereinthe morphinan and pharmacologically active agent are provided insustained release dosage form.
 10. The method of claim 5 wherein themorphinan and the pharmacologically active agent are administeredorally, intravenously, intramuscularly, subcutaneously, transdermally orintrathecally.
 11. A method of decreasing micturition frequency in amammal which comprises administering to a mammal a micturitiondecreasing amount of a morphinan selected from the group consisting ofdextromethorphan, dextrorphan and pharmaceutically acceptable saltsthereof.
 12. The method of claim 11 wherein the morphinan is containedin a pharmaceutically acceptable vehicle.
 13. The method of claim 11therein the morphinan provided is provided in sustained release dosageform.
 14. The method of claim 11 wherein the morphinan is administeredorally, intravenously, intramuscularly, subcutaneously, transdermally orintrathecally.
 15. The method of claim 11 which further comprisesadministering a pharmacologically active agent selected from the groupconsisting of anticholinergic, sympathomimetics, tricyclicantidepressants, antispasmodics, direct-acting bladder smooth musclerelaxants, estrogens, compounds having estrogen-like activity estrogen,and any combination of the foregoing.
 16. The method of claim 15 whereinthe pharmacologically active agent is selected from the group consistingof oxybutynin, atropine, propantheline, terodiline, dicyclomine,ephedrine, pseudoephedrine, phenylpropanolamine, amitriptyline,imipramine, doxepin, an estrogen and flavoxate.
 17. The method of claim15 wherein the morphinan is administered concurrently with thepharmacologically active agent.
 18. The method of claim 17 wherein themorphinan and pharmacologically active agent are contained in apharmaceutically acceptable vehicle.
 19. The method of claim 15 whereinthe morphinan and pharmacologically active agent are provided insustained release dosage form.
 20. The method of claim 15 wherein themorphinan and the pharmacologically active agent are administeredorally, intravenously, intramuscularly, subcutaneously, transdermally orintrathecally.
 21. A method of treating interstitial cystitis whichcomprises administering to a mammal exhibiting interstitial cystitis aneffective amount of a morphinan selected from the group consisting ofdextromethorphan, dextrorphan and pharmaceutically acceptable saltsthereof.
 22. The method of claim 21 which further comprisesadministering a pharmacologically active agent selected from the groupconsisting of anticholinergics, sympathomimetics, tricyclicantidepressants, antispasmodics, direct-acting bladder smooth musclerelaxants, estrogens, compounds having estrogen-like activity, and anycombination of the foregoing.
 23. The method-of claim 22 wherein thepharmacologically active agent is selected from the group consisting ofoxybutynin, atropine, propantheline, terodiline, dicyclomine, ephedrine,pseudoephedrine, phenylpropanolamine, amitriptyline, imipramine,doxepin, estrogens and flavoxate.
 24. A composition comprising at leastone morphinan selected from the group consisting of dextromethorphan,dextrorphan and the pharmaceutically acceptable salts thereof and atleast one pharmacologically active agent selected from the groupconsisting of anticholinergics, sympathomimetics, tricyclicantidepressants, antispasmodics, direct-acting bladder smooth musclerelaxants, estrogens, compounds having estrogen-like activity, and anycombination of the foregoing.
 25. The composition of claim 24 whereinthe pharmacologically active agent is selected from the group consistingof oxybutynin, atropine, propantheline, terodiline, dicyclomine,ephedrine, pseudoephedrine, phenylpropanolamine, amitriptyline,imipramine, doxepin, estrogen an and flavoxate.
 26. The composition ofclaim 24 in sustained release dosage form.
 27. The composition of claim25 in sustained release dosage form.